The present disclosure is generally directed to a biomarker panel for diagnosis of chronic graft-versus-host disease (cGVHD) and to methods of diagnosing cGVHD using the biomarker panel. Particularly, the biomarker panel is a four-biomarker panel including ST2, CXCL9, MMP3, and OPN.
Chronic graft-versus-host disease (cGVHD) remains the major contributor to morbidity and mortality for survivors of allogeneic hematopoietic cell transplant (HCT), reportedly occurring in 30-70% of adults and children surviving more than 100 days. It is also the leading cause of non-relapse mortality (NRM) occurring more than 2 years after the HCT for malignant disease. cGVHD usually starts more than 3 months after a transplant, and can last a lifetime. Chronic symptoms may include: dry eyes or vision changes; dry mouth, white patches inside the mouth, and sensitivity to spicy foods; fatigue, muscle weakness, and chronic pain; joint pain or stiffness; skin rash with raised, discolored areas, as well as skin tightening or thickening; shortness of breath; vaginal dryness; and weight loss.
cGVHD occurs in allogeneic bone marrow transplantation recipients when donor immune cells recognize the host tissues as foreign and attack them. This reaction can be minimized by carefully matching the donor and host tissues and using prophylactic immunosuppression, but it is still one of the leading causes of morbidity and mortality for survivors of allogeneic hematopoietic cell transplant. Pre-transplant clinical or transplant characteristics have minimal ability to predict GVHD outcomes. Currently, cGVHD is diagnosed by clinical symptoms using the NIH chronic GVHD consensus criteria as set forth in National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report, Jagasia et al., Biol. Blood Marrow Transplant, 2015, 21(3):389-401. Particularly, for diagnosis, the following criteria must be met: (1) distinction from acute GVHD; (2) presence of at least 1 diagnostic clinical sign of chronic GVHD or presence of at least 1 distinctive manifestation confirmed by pertinent biopsy or other relevant tests; and (3) exclusion of other possible diagnoses. Therefore, at the time of diagnosis, patients can already have substantial organ damage.
Despite multiple clinical trials investigating innovative treatments for cGVHD, the standard treatment for the last 30 years remains predominantly steroids, with or without calcineurin inhibitors, that is incompletely effective, is associated with infections and long-term risks of toxicity. Accordingly, there has been a push in the art to develop biomarker immunoassays for conclusive GVHD diagnosis before the onset of symptoms, because in the event that a patient develops GVHD, it is critically important to treat them early to prevent organ damage.